MicroRNA-1912 regulates cholesterol homeostasis by targeting PCSK9

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein (LDL) receptor (LDLR) and promotes degradation of LDLR, regulating cholesterol homeostasis. Previous studies have reported several microRNAs (miRNAs) that regulate PCSK9 expression; however, evidence for these effects in animal models remains controversial. This study aimed to explore miRNA candidates for PCSK9 regulation and to validate the most potent miRNA for this regulation <i>in vivo</i>. Bioinformatic algorithms identified miRNAs regulating PCSK9, with miR-224 and miR-1912 showing a high probability of targeting PCSK9. Treatment with miR-224 and miR-1912 significantly reduced PCSK9 mRNA and protein levels and led to an increase in LDLR protein expression, resulting in increased uptake of LDL particles in HepG2 cells, with miR-1912 showing a greater effect than miR-224. Specific interactions of miR-1912 and miR-224 with the 3' untranslated region (UTR) of <i>PCSK9</i> mRNA were confirmed by a luciferase reporter assay and site-directed mutagenesis analysis of the predicted seed region. In transgenic mice expressing liver-specific human PCSK9 with its 3' UTR, administration of miR-1912 mimics resulted in a reduction of plasma total cholesterol levels as determined by fast protein liquid chromatography following hepatic delivery. These findings highlight miR-1912 as a promising therapeutic candidate for hypercholesterolemia via targeted, post-transcriptional regulation of <i>PCSK9</i>.